ALBERT

Description: Background Although azacitidine (AZA) improves survival over conventional treatments in higher risk MDS (Lancet Oncol, 2009), median overall survival (OS) with AZA is only about 2 years, the CR+PR rate about 30%, and further improvements are needed. Gene hypomethylation appears to be a major mechanism of action of AZA but, with the typical 7 days of administration every 28 days, reversal of gene hypomethylation is seen at the end of each cycle (Braiteh F, Clin Cancer Res 2008), suggesting that increasing the number of treatment days could improve AZA results. This trial tested the hypothesis that an AZA regimen with more days of drug administration (ie using the standard daily dose of 75 mg/m2, but during 5 days every 14 days ) could increase the response rate, and that this improvement could translate into better OS. Methods Patients (pts) aged 18-75 years with ECOG performance status (PS) of 0–2 and no major comorbidities preventing administration of an intensified regimen of AZA, with IPSS int-2 or high MDS, CMML with WBC 〈 13,000/mm3 and marrow blasts 〉 10% , and AML with 20-30% marrow blasts (ie EU label for AZA) who had received no prior treatment for their MDS/AML except ESAs could be included. Treatment consisted of AZA 75mg/m2/d for 5 days every 14 days for 4 cycles (AZA-14, cycles 1-4). Patients achieving CR or PR then received 4 cycles of AZA 75mg/m2/d during 5 days every 21 days (AZA-21, cycles 5 to 8) followed by classical cycles of AZA 75mg/m2/d for 7 days every 28 days, to be continued until progression/relapse or toxicity arose. This schedule corresponded to a 20% increase in the number of days of AZA during the first 8 weeks of treatment. Patients not obtaining CR or PR after the initial 4 cycles of AZA-14 received 4 additional cycles of AZA 14 (cycles 5 to 8). Patients not obtaining CR, PR or HI after 8 cycles of AZA-14 were taken off-study. The primary endpoint was response after 4 and 8 cycles (IWG 2006 criteria). We present here the 1st interim analysis of the trial based on the first 22 patients/26 inclusions. Median [IQR] are reported unless specified. Results One patient was excluded for consent withdrawal. 21 patients (M/F: 14/7, median age 66) were enrolled between 2011 and 2013, including 2 RCMD, 2 RAEB1, 10 RAEB2 and 5 AML (with 20 to 30% marrow blasts). Karyotype (IPSS) was favorable in 9 pts, intermediate in 4 patients and unfavorable in 8 pts. Median marrow blast was 13% (range 9.5-15), baseline platelet count was 71 G/l (37-204) including 33% with platelet

Description: Background: Although azacitidine (AZA) improves survival over conventional treatments in higher risk MDS (Lancet Oncol, 2009), median overall survival (OS) with AZA is only about 2 years, the CR+PR rate about 30%, and further improvements are needed. Gene hypomethylation appears to be a major mechanism of action of AZA but, with the typical 7 days of administration every 28 days, reversal of gene hypomethylation is seen at the end of each cycle (Braiteh F, Clin Cancer Res 2008), suggesting that increasing the number of treatment days could improve AZA results. This trial tested the hypothesis that an AZA regimen with more days of drug administration (ie using the standard daily dose of 75 mg/m2, but during 5 days every 14 days) could increase the response rate, and that this improvement could translate into better OS. Methods: Patients (pts) aged 18-75 years with ECOG performance status (PS) of 0-2 and no major comorbidities preventing administration of an intensified regimen of AZA, with IPSS int-2 or high MDS, CMML with WBC 〈 13,000/mm3 and marrow blasts 〉 10% , or AML with 20-30% marrow blasts (ie EU label for AZA) who had received no prior treatment for their MDS/AML except ESAs could be included. Treatment consisted of AZA 75mg/m2/d for 5 days every 14 days for 4 cycles (AZA-14, cycles 1-4). Patients achieving CR or PR then received 4 cycles of AZA 75mg/m2/d during 5 days every 21 days (AZA-21, cycles 5 to 8) followed by classical cycles of AZA 75mg/m2/d for 7 days every 28 days, to be continued until progression/relapse or toxicity arose. This schedule corresponded to a 30% increase in the number of days of AZA during the first 3 months of treatment. Patients not obtaining CR or PR after the initial 4 cycles of AZA-14 received 4 additional cycles of AZA 14 (cycles 5 to 8). Patients not obtaining CR, PR or HI after 8 cycles of AZA-14 were excluded from the trial. The primary endpoint was response after 4 and 8 cycles (IWG 2006 criteria). Median [IQR] are reported unless specified. Results: 27 patients were included, of whom 1 was excluded for consent withdrawal. 26 patients (M/F: 19/7, median age 66) enrolled between 2011 and 2013, were thus analyzed, including 1 ARSI, 2 RCMD, 3 RAEB1, 13 RAEB2, 2 CMML and 5 AML (with 20 to 30% marrow blasts). Karyotype (IPSS) was favorable in 11 pts, intermediate in 6 patients and unfavorable in 9 pts. Median marrow blast was 13.5% (IQR 9.7-18.0), baseline platelet count was 72.5 G/l (43.5-177.0) including 69% with platelet

Description: Background The treatment algorithm is still limited in WM as very few drugs were approved based on studies dedicated to WM patients. In 2015, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib became the first drug approved to treat WM (Treon et al, 2015). However, a subset of patients (pts) relapses due to acquired resistance. Therefore there is a great medical need to develop chemo-free approaches based on a better understanding of the biology of the disease to increase all survival endpoints. MYD88L265P also promotes activation of the phosphatidylinositol-3-kinase (PI3K) pathway Gopal et al. reported 80% ORR in 10 patients with WM, refractory to anti-CD20 and alkylating agents, treated with idelalisib (a PI3K inhibitor) (NEJM, 2014). A previous study was stopped because of high incidence of hepatotoxicity (Castillo, Leuk lymphoma, 2017). So we design our trial with a Bayesian analysis of adverse events. Aims We initiated a prospective, single-arm phase II study to evaluate efficacy and safety of idelalisib in combination with obinutuzumab in pts with R/R WM in need of treatment. (NCT02962401). Methods During the induction phase, idelalisib was given continuously 150 mg BID PO in association with IV obinutuzumab 100mg day 1, 900mg day 2 then 1000mg fixed dose day 8, 15 of cycle 1 and every day 1 of cycles 2 to 6 (28-days cycle). Then during the maintenance phase, idelalisib was given alone for a maximum of 2 years. Pts were closely monitored for infusion related reactions (IRR). Adverse events were graded per CTCAE v.4.0. Response was assessed based on IWWM6 criteria. The analyses of PFS, primary endpoint of this study, were based on the intent-to-treat population. The safety analysis was designed according to Bayesian estimation of the probability of grade 3 or more adverse events. Roche and Gilead provide drugs and funding. Results Fifty pts were enrolled between February 2017 and July 2018 but 49 pts were analyzed (1 screen failure). We present the results of early efficacy and safety, assessed after the induction phase. At time of analysis, median follow-up was 18.3 months (range 14.9-23 months). Median age was 71 years (range 50-83 years) and 36 pts (73%) were men. MYD88 mutation was present in 47 pts (96%). Indications to treat were anemia (31%), anemia + thombocytopenia (11%), constitutional symptoms (11%), rapid evolution of monoclonal component (11%), hyperviscosity syndrome (9%), thrombocytopenia (6%), extramedullary disease (8%) and neuropathy (6%) (data not available for 2 pts). Median number of previous lines of therapy was 1 (range 1-3), and only 1 patient was previously exposed to BTK inhibitors. At baseline, median serum IgM was 2.193 mg/dl (range 0.19-9.2), median bone marrow involvement was 55% (range 10-90, n=25) and median hemoglobin was 10 g/dl (range 6.5-13.8). Thirty-four pts responded, 13 after 3 cycles and 21 after 6 cycles. The overall response rate (ORR) was 90% and the major response rate (MRR) was 76% (no CR, VGPR: 8%, PR: 68%, MR: 14%, SD: 8%, and progression: 3%). The correlation between responses and genomic status using ultra deep next generation sequencing will be communicated later. Median PFS was 25.2 months. The1-year and 2-year PFS were 90% [IC95%: 80; 100] and 70% [IC95%: 53; 93] respectively. The1-year and 2-year OS were 98% [IC95%: 94; 100] and 85% [IC95%: 69; 100] respectively. Three pts died (1 before starting treatment, 1 from macrophage activation syndrome, 1 after stopping treatment). Median duration of response was 21.8 months. No flare, no IRR grade ≥ 2, no tumor lysis syndrome were observed. Thirty-five pts experienced at least one grade ≥ 3 adverse events (AE) or serious adverse events (SAE), with an estimated probability of 72.5% (95% credibility interval, 59.5-83.9) and a probability of 1 that more than 30% of pts experience at least 1 grade 3 AE. Events that occurred most frequently included hepatotoxicity (23 AE, 5 SAE, 20%), diarrhea (4 AE, 10 SAE; 10%), skin (3 AE, 3 SAE, 4%), infections (0 AE, 5 SAE, 4%), neutropenia (41 AE, 29%), anemia (7 AE, 5%), thrombopenia (6 AE, 4%). This trial is ongoing with 29 pts who started idelalisib maintenance. Conclusion This is the first study evaluating combination with idelalisib + obinutuzumab and the first chemo-free fixed-duration association in R/R WM pts. The combination has clinical activity with 90% ORR and 76% MRR. Median PFS was 25 months. Most of grade ≥ 3 AE or SAE are hepatotoxicity, diarrhea and neutropenia as expected with idelalisib. Figure Disclosures Tomowiak: Abbvie: Honoraria; Janssen: Honoraria. Perrot:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Amgen: Honoraria; takeda: Honoraria; jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau.

Description: Abstract 2320 Poster Board II-297 In 1996, we initiated a multicenter prospective trial where patients aged under 56 with newly diagnosed symptomatic MM were randomly assigned up-front to receive either a single HDT (HDT1) or two sequential HDT (HDT2). In addition, all patients were independently randomized to be transplanted with unselected ABSC (unselected arm) or CD34-enriched ABSC (CD34 arm). We presented here updated data of this factorial 2*2 design trial, based on a median follow-up of 123 months.In all cases, patients first received one or 2 courses of high dose steroid containing regimens and ABSC were thereafter mobilized by cytoxan (CTX) (4 g/m2) and lenograstim (10 mg/kg/d). When appropriate (CD34 arm), part of collected ABSC were selected using the Isolex®300i system. The selection procedure resulted in a median purity of 95% (65-100) and in a more than two log tumor cell depletion. In the HDT1 arm, HDT was preceded by 3 monthly courses of a VAD-like regimen and combined a multi-drug regimen (carmustine, etoposide, melphalan 140 mg/m2 (MLP 140) and CTX 60 mg/kg) with a TBI (12 grays in 6 fractions). Patients treated in the HDT2 arm received MLP 140 alone (always supported by unselected ABSC) followed 2 to 3 months later by a second MLP 140 combined with etoposide (30 mg/kg) and 12-gray TBI. In both arms, TBI including HDT were supported with unselected or CD34 enriched ABSC. Two hundred and twenty-five patients were included in the study. Baseline characteristics of the four groups were close. All analyses were performed in intent to treat basis. In HDT groups, treatment completion rates were satisfactory, with 6/112 transplants not performed in the HDT1 group (allotransplant n=1, refusal n=1, mobilisation failure n=1, early death due to disease progression n=3) and 9/113 second transplant not performed in the HDT2 group (allotransplant n=2, mobilisation failure n=3, relapse post first transplant n=1, early death due to disease progression n=3). In the HDT1 and HDT2 groups, median time to TBI-including transplant was 4 months and 4.5 months, respectively.Present analysis did not show any significant difference in terms of early mortality, disease response and outcome of patients included in the two HDT groups. Early death rates (within 9 months post randomization, including toxic deaths and fatal progressive diseases) were 12% and 7% in the HDT1 and the HDT2 arms, respectively. At one year post-randomization, 32 (35 %) patients in the HDT1 and 32 (37 %) patients in the HDT2 groups were still in unmaintained CR or VGPR. The 2 OS curves were not statistically different (p= 0.60 by the log rank test), neither the EFS curves (p= 0.61). There was no significant interaction between selection CD34 and HDT in terms of outcomes. There was no evidence for benefit of CD34 selection as compared to the use of unselected ABSC. Of note, in the CD34 selected group, incidence of severe infections was increased. In conclusion, with a 10-years median follow-up, results of this randomized trial did not show any significant benefit of single HDT versus tandem HDT. Disclosures: No relevant conflicts of interest to declare.